This invention relates to the general field of controlling excessive levels of bilirubin.
In the human body, bilirubin is produced by the breakdown of cyclic tetrapyrroles, particularly hemoglobin. Excessive bilirubin concentrations, manifest as jaundice, can cause irreversible damage to the central nervous system.
Ordinarily, bilirubin concentration is controlled as bilirubin is filtered from the blood by the liver, where it is conjugated with glucuronic acid. The bilirubin glucuronic acid conjugate (referred to hereafter as "conjugated bilirubin") is excreted to the small intestine via the common bile duct. Bacterial flora reduce conjugated bilirubin, which is then excreted in the stool.
Excessive bilirubin is common in infants for a number of reasons including a high rate of hemolysis, immaturity of liver function necessary to form conjugated bilirubin, obstruction of the bilary system, and the absence of intestinal flora to reduce bilirubin conjugate. In the absence of intestinal flora and their reducing enzymes, conjugated bilirubin may be deconjugated, and the resulting unconjugated bilirubin may be reabsorbed by the intestine, increasing serum bilirubin concentrations.
Various therapies for excessive bilirubin are known. The two most common treatments for neonatal jaundice are phototherapy and exchange transfusion.
In phototherapy, bilirubin is converted to more readily excreted photoisomers by exposing the infant to blue light. See, e.g., McDonagh et al., Science 208:145-151 (1980); and McDonagh et al., J. Clin. Invest., 66: 1182-1185 (1980). Phototherapy is relatively slow, and long term conseguences of blue light exposure are not known.
For severe cases of jaundice (plasma bilirubin &gt;15 mg/dl), it may be necessary for the infant to undergo exchange transfusion. Exchange transfusion involves the replacemnmt of the infant's blood with bilirubin-free adult blocd. This procedure presents potentially fatal risks, including blood damage, fluid shifts, and risk of transmission of infectious diseases.
Other potential treatments in development stages include extracorporeal devices, such as hemoperfusion, which utilize resins to adsorb bilirubin. In hemoperfusion, the blood or plasma of a patient is passed through an affinity column. The column, which usually consists of a bed of small particles, binds bilirubin which is in the blood; the cleansed blood or plasma is then returned to the patient. For instance, Freston et al., Kidney Intern. 10: S-229 (1976), and Sideman et al., Am. Soc. Art. Intern. Org. J., 4, 164 (1981), report removal of bilirubin from artificial plasma by hemoperfusion with uncoated and cellulose-coated carbon as well as with serum albumin coated beads. Lavin et al., Science:230 (4725): 543 (1985) describe an extracorporeal column containing immobilized bilirubin oxidase to reduce serum bilirubin concentration. Bilirubin oxidase catalyzes the degradation of bilirubin to biliverdin and biliverdin to other non-toxic products.
Odell et al., Ped. Res., 17, 810 (1983), describe the use of agar as a nonspecific bilirubin adsorbent. Enteral administration of agar was shown to increase the efficacy of phototherapy in the treatment of neonatal hyperbilirubinemia. The binding capacity of agar for bilirubin was positively correlated to the sulfate and to the calcium content of the agar as described by Poland and Odell, Proc. Soc. Exp. Biol. Med., 146: 1114 (1974).